ASNS (asparagine synthetase)

2008-11-01   Philip L Lorenzi , Michael C Ryan , Ogechi N Ikediobi , John N Weinstein 





ASNS is encoded on chromosome 7 and has 14 exons. The promoter begins 173 bases upstream of the start codon, which is on exon 4, with three GC-rich sequences (GC-I, GC-II, and GC-III) followed by two nutrient sensing response elements, NSRE-1 (ATGATGAAA; at nt -70) and NSRE-2 (GTTACA; at nt -49). The stop codon is on exon 14.


The full length transcript (RefSeq variant 1; NM_133436 on Fig1) is 2348 bp long. Ten alternative splicing isoforms have been reported with most variation occurring primarily in the 5UTR.
Various forms of cellular stress, including nutrient deprivation, lead to increased ASNS transcription. One component of that mechanism includes translation of the activating transcription factor family of proteins (ATF2, ATF3, ATF4, ATF5, and ATF6), all of which increase ASNS transcription through binding to NSRE-1 and/or NSRE-2. TRB3 is a negative feedback regulator of ATF4-dependent transcription, and C/EBP-beta is a negative regulator of ATF5-dependent transcription. DDIT3/CHOP is also a negative regulator of ASNS transcription.
ASNS has also been reported to be a significant target of transactivation by mutant p53, whereas wild-type p53 inhibits transcriptional activation of the NSREs.
ASNS mRNA has been shown to exhibit a half-life of 9 h and periodic, clock-like up-regulation every around 35 min in cell culture.


Atlas Image
Representation of the ASNS gene, its mRNA splice variants, and its protein isoforms.
Each unique splice variant is identified by an accession number on the left-hand side. Exons are numbered at the top of the image. Lighter green indicates UTRs, and dark green indicates protein-coding regions. Exons are drawn to scale. Intronic sections are indicated by thin green lines and are not drawn to scale.


Transcripts NM_001673, NM_133436, NM_183356, BC008723, BC014621, BT007113, and M27396 encode a common 561 aa (64 kDa) ASNS protein sequence. Transcripts AK302189 and M15798 encode 540 aa N-terminally truncated proteins that differ in sequence between amino acids 312-322 and 332-339. Transcript AK302242 encodes a 478 aa isoform that is further truncated at the N-terminus.


Only the 561 aa isoform has been experimentally confirmed, and it has been found to be up-regulated by nutrient deprivation. Its half-life is reported to be 43-46 h.


ASNS protein is cytoplasmic, but prediction algorithms also predict a small fraction of nuclear localization.


ASNS catalyzes the synthesis of asparagine from glutamine and aspartic acid. In addition to providing asparagine for global protein synthesis, ASNS expression appears to be required for the transition from G1 to S phase of the cell cycle.


The 561 aa ASNS isoform has 29% identity with a protein called asparagine synthetase domain containing 1 (ASNSD1) that is 643 aa in length and encoded by a transcript (NM_019048) produced by chromosome 2.



A total of 136 SNPs have been reported in the ASNS gene region thus far, and 9 of these are coding SNPs: C1820A (P547H); C1399T (R407X); C1389G (L403L); 1299G (G373-frameshift); G1009A (A277T); T809A (V210E); A546T (A122A); G524C (C115S); C324T (H48H). Of those nine coding SNPs, only V210E has been validated by multiple independent groups including the HapMap Project. None of the SNPs has thus far been clinically associated with a disease or drug response phenotype.


All reported SNPs appear to be of germline origin.


None of the reported SNPs have been associated with tumor initiation or progression.

Implicated in

Entity name
Chemotherapeutic efficacy of L-asparaginase. The enzyme-drug L-asparaginase has been used since the 1970s to treat acute lymphoblastic leukemia. ASNS expression has been found to be correlated with L-asparaginase efficacy in leukemia cell lines, in leukemia primary tumor samples, and more recently in cancer cell lines from other tissues of origin. Silencing ASNS expression by RNAi has indicated the L-asparaginase/ASNS relationship is causal and suggests that ASNS expression may be useful as a predictive clinical biomarker of L-asparaginase efficacy.
Low ASNS expression suggests good response to L-asparaginase.
Entity name
Protein and/or amino acid deprivation
The Amino Acid Response (AAR) pathway is triggered by protein and/or amino acid deprivation, which leads to a build up of uncharged tRNA, which bind to and activate the GCN2 kinase, which in turn phosphorylates eIF2alpha. P-eIF2 alpha suppresses global translation initiation yet causes an increase of ATF4 synthesis from preexisting mRNA. ATF4 stimulates transcription of a variety of stress-response genes, including ASNS.


Pubmed IDLast YearTitleAuthors
114154662001Asparagine synthetase expression alone is sufficient to induce l-asparaginase resistance in MOLT-4 human leukaemia cells.Aslanian AM et al
108562892000Activation of the human asparagine synthetase gene by the amino acid response and the endoplasmic reticulum stress response pathways occurs by common genomic elements.Barbosa-Tessmann IP et al
15434961992TSH is able to induce cell cycle-related gene expression in rat thyroid cell.Colletta G et al
188400952009Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the ATF6 and IRE1/XBP1 arms of the pathway.Gjymishka A et al
16827981991Regulation of asparagine synthetase gene expression by amino acid starvation.Gong SS et al
171852292006An inhibitor of human asparagine synthetase suppresses proliferation of an L-asparaginase-resistant leukemia cell line.Gutierrez JA et al
173692602007TRB3 inhibits the transcriptional activation of stress-regulated genes by a negative feedback on the ATF4 pathway.Jousse C et al
188521152008Asparagine synthetase is a predictive biomarker of L-asparaginase activity in ovarian cancer cell lines.Lorenzi PL et al
167565052006Asparagine synthetase chemotherapy.Richards NG et al
150771942004Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes.Scian MJ et al

Other Information

Locus ID:

NCBI: 440
MIM: 108370
HGNC: 753
Ensembl: ENSG00000070669


dbSNP: 440
ClinVar: 440
TCGA: ENSG00000070669


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Alanine, aspartate and glutamate metabolismKEGGko00250
Alanine, aspartate and glutamate metabolismKEGGhsa00250
Metabolic pathwaysKEGGhsa01100
Metabolism of proteinsREACTOMER-HSA-392499
Unfolded Protein Response (UPR)REACTOMER-HSA-381119
PERK regulates gene expressionREACTOMER-HSA-381042
ATF4 activates genesREACTOMER-HSA-380994
Metabolism of amino acids and derivativesREACTOMER-HSA-71291
Amino acid synthesis and interconversion (transamination)REACTOMER-HSA-70614

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA448492asparaginaseChemicalLiterature, MultilinkAnnotationassociated24268318


Pubmed IDYearTitleCitations
173802072007Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase.93
153855332004Amino acid deprivation induces the transcription rate of the human asparagine synthetase gene through a timed program of expression and promoter binding of nutrient-responsive basic region/leucine zipper transcription factors as well as localized histone acetylation.87
119609872002ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.80
234039462013Asparagine synthetase: regulation by cell stress and involvement in tumor biology.65
189407922008C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene.61
241390432013Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy.34
170884362006Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells.29
188521152008Asparagine synthetase is a predictive biomarker of L-asparaginase activity in ovarian cancer cell lines.29
188521152008Asparagine synthetase is a predictive biomarker of L-asparaginase activity in ovarian cancer cell lines.29
123516262002Differences in the molecular mechanisms involved in the transcriptional activation of the CHOP and asparagine synthetase genes in response to amino acid deprivation or activation of the unfolded protein response.26


Philip L Lorenzi ; Michael C Ryan ; Ogechi N Ikediobi ; John N Weinstein

ASNS (asparagine synthetase)

Atlas Genet Cytogenet Oncol Haematol. 2008-11-01

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